Here is an illustration from Goodman, 2014 of the mTORC1 signalling cascade:

As we can see in this illustration, mTOR connects to protein synthesis and cell growth via different pathways. This means that mTOR influences hypertrophy indirectly. Kind of like how the engine of a car is necessary to make it move, but you still need other “pathways” like the steering wheel, cooling mechanisms, clutch, etc. to functionally drive the car.

mTOR associates not only with MPS, but muscle protein breakdown (MPB) as well. As you may recall from my ASM article, MPB has a catabolic effect. Researchers like Goodman (2014) state that mTOR is inversely connected to MPB. This means mTOR deactivates MPB. By doing this, mTOR could help prevent catabolism (Sandri, 2013).

Metabolism and energy balance: how amino acids and glycogen affect mTOR and AMPK

According to this theory, we will likely experience atrophy in periods of energy deprivation. However, the body tries to bounce back from energy deficits. One of the ways it does this is by upregulating glycogen resynthesis in muscle cells after exercise (Aragon & Schoenfeld, 2013). By supplying carbs post-exercise when the cell is energy depleted, we could maximise glycogen resynthesis. However, this probably isn’t something you need to focus on if you’re in an energy surplus. It could be more important if you are in a deficit or do several workouts per day (more on this in a future article about nutrient timing).

As I mentioned, cells always try to maintain cellular energy homeostasis (Carbone, 2012; Bond, 2016). By feeding, we diminish catabolic response that come from AMPK activation (Lopez et al., 2016). This is because macronutrients like protein activate mTOR, which in turn cross-talks with AMPK. Together, they control whole-body energy balance (Morentin et al., 2014; Cai et al., 2015; Hardie, 2011; Xu et al., 2012; Lopez et al., 2016). Some studies find that mTOR and AMPK influence your hunger and activity levels, but most of these studies are done on animals as of date. There are ethical considerations when playing around with mTOR in humans, since it affects the body in a lot of different ways.

Immune system

mTOR plays an important role in adaptive immunity (Araki et al., 2011). This system specialises in eliminating specific pathogens (i.e. viruses, bacteria). There’s also the innate immune system that functions a bit differently. This system produces non-specific responses to pathogens, like inflammation. And since mTOR is connected to both systems, it is also regulates part of the inflammatory response.

This means that mTOR activation isn’t always directly related to hypertrophy. This is a confounding variable that needs to be controlled for in mTOR hypertrophy research. In different terms, let’s say there’s a ball rolling down a hill. You know that your friend Frank went up the hill a few minutes ago, so you assume that Frank kicked the ball down the hill (classic Frank). This means you have created a causal relationship between Frank (the cause) and the ball rolling down the hill (the effect). However, it’s also possible that a strong surge of wind pushed the ball down the hill. Frank’s visibility and the wind become confounding variables we need to control for. So the next time a ball rolls down a hill, you need to be certain that you can see Frank kicking the ball, but you should also check that the wind isn’t blowing very hard at that moment. Now replace yourself with researchers, Frank with amino acids/resistance training, and the ball with mTOR, and the wind with alternative mTOR activation (i.e. immune system-related activation) and you can see my concern; we need to control for how mTOR is activated, and what type of protein synthesis it affects.

With that said, 2015 review by Weicchart et al., notes that mTOR activates the innate immune system as well as whole-body protein synthesis at the same time. This might seem weird, because why would infections cause gains (assuming MPS elevations = gains)? There are several reasons why they wouldn’t, one of them being that whole-body protein synthesis does not predict hypertrophy (Tzur, 2016). Myofibrillar protein synthesis is a better proxy for gains if measured alongside MPB. Ultimately this means that mTOR can active MPS in circumstances that are not hypertrophy-specific. At least this is what the animal research suggests. Another argument for mTORs connection to the immune system is that mTOR inhibition leads to immunosuppression in animals (Weichhart et al., 2015).

Other functions

Fat sTORage

I won’t go into great detail about mTOR’s role in fat storage in this article, but it should suffice to say that mTOR regulates adipose tissue in many animals, and possibly humans 2 (Woods et al., 2008; Mannaa et al., 2013)

mTOR has many important roles in the body. I think it is important to point this out because I usually see mTOR described as a hypertrophy switch and then nothing else is said of its multiple, complicated functions. It should be clear that mTOR does not function on it’s own; it’s connected to many other mechanisms.

Limitations of mTOR research

Some of the mTOR and AMPK research cited in this section is done on animals. Animal research is not directly applicable to humans 3. But this doesn’t mean animals and humans are completely different 4. In fact, some researchers think there is considerable overlap between species because they have many biological mechanisms in common 5. So there is definitively a basis for interspecies comparison. Even so, in the next section we completely discard animal science in favour of human research.

[expand title=”3“][themify_icon icon=”fa-quote-left”] Experimental animal models are not fully reliable [but] reproduce at least some aspects of human disease. Expression and activation pattern of AMPK isoforms differs between rodent and human muscle and between muscle fiber types (149, 150). Furthermore, sex difference in muscle AMPK activation has been observed in humans, probably due to sex specific muscle morphology (higher proportion of type 1 muscle fibers in women) (Viollet et al., 2009)[/expand] [expand title=”4“][themify_icon icon=”fa-quote-left”]AMPK is a cellular energy sensor that exists in almost all eukaryotes (Hardie, 2011)[/expand] [expand title=”5“][themify_icon icon=”fa-quote-left”] The recent evidence (…) suggests that the problem of [caloric restriction] longevity can essentially be reduced to a cell-biological one. If we unlock the mechanisms of [caloric restriction] in lower organisms, we might be much closer to solving that problem in mammals than previously suspected (Bishop and Guarente, 2007)[/expand]

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Human hypertrophy and mTOR: applied research

We’ve discussed whether mTOR activation could lead to gains from a molecular point of view. But molecular logic is only one perspective. We need to look at the applied science; does mTOR activation lead to hypertrophy in real life human subjects?

I will present both sides of the argument independently, then critically evaluate the research that supports or challenges mTOR as a predictor of hypertrophy.

Before we start, let’s clarify some issues on causation and correlation:

What does it mean that mTOR “predicts gains”? In short, the assumption is that a greater degree of mTOR activation leads to more hypertrophy. A logical follow-up to this assumption is that mTOR deactivation should lead to atrophy (or at least non-hypertrophy). We also assume that if mTOR is causally connected to gains, then any activation of mTOR should lead to hypertrophy, even if there is no exercise-related stimulus. If mTOR activation does not lead to hypertrophy, it is not causally connected to gains. We have a correlation but no causation if mTOR is connected to gains only in some circumstances. And if there’s only a correlation, then mTOR’s predictive powers aren’t as strong, because we would need to control for other factors that would influence hypertrophy. Ideally we would like to be able to quantify it (Rennie et al., 2004).

For example: “x% mTOR activation leads to x amount of LBM gains”

The case for mTOR

We’ve already partially established how mTOR works, but let’s dig deeper into the theory. Let’s start with how we know whether mTOR is “activated” or not.

As per the illustration further up in this article, mTOR is connected to various downstream effectors like p70S6K. These factors can be phosphorylated, which is a complicated way of saying they can be switched on or off (Laplante and Sabatini, 2009). When researchers want to see if mTOR is activated, they usually measure the activity of enzymes like p70S6K. In other words they measure mTOR activation indirectly. There are many different ways of activating mTOR and downstream effectors (Hay and Sonenberg, 2004) but since I don’t want to write War and Peace part 2: The Paths to mTOR, I’ll stick to the effector that’s most relevant to us: p70S6K

Let’s start with a study from 2006, by Dreyer et al. where they put 11 untrained men and women through 6 resistance training sessions and measured mTOR downstream signals like p70S6K and 4E-BP1. They also looked at the mTOR inhibitor AMPK and compared the results to mixed muscle protein synthesis*. The researchers found that AMPK was activated during exercise, as is to be expected per our discussion on energy sensing and cellular energy depletion. Exercise lowered MPS temporarily. One to two hours post-exercise, mTOR downstreams were activated alongside increased MPS. So there is a correlation between mTOR and MPS.

[expand title=”However, there are some issues with this study (click if you want to go in-depth)”]

amino acid concentrations [did not regulate] mTOR signalling during and after resistance exercise, since mTOR phosphorylation was increasing while amino acid concentrations were decreasing.

This finding is a bit of a surprise since we would expect to see increased amino acid concentrations with increased mTOR activity.

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Another study from 2008 got six untrained male students to participate in a 14-week resistance training program that added 40kg (mean) to their squat and 20kg (mean) to their bench (Terzis et al., 2008). They measured p70S6K and found an association with mTOR activation and strength and hypertrophy gains. However, the authors acknowledged that p70S6K may not be correlated to gains in trained athletes. Several other research teams agree that trained athletes respond differently to anabolic signals 6 (Coffey et al., 2005; Gonzalez, 2015; Gonzalez et al., 2015a).

The low participation number was corrected (N=50) in a similar study by Kumar et al., 2009. This study has 360+ citations and is perhaps one of the hallmark studies of mTOR and MPS. They found a correlation between p70s6k in myofibrillar MPS and gains in young subjects. They concluded that older people had anabolic resistance, because of their reduced anabolic signalling. Sadly, Kumar et al. didn’t directly measure hypertrophy.

Things were turned on their head a year later when Terzis et al. published a study with eight untrained men doing 14 weeks of resistance training (Terzis et al., 2010). They discovered that p70s6K was correlated with muscle hypertrophy (but not strength) after a bout of training, while mTOR activation was not 7. This is slightly “shocking” given that p70s6K was previously considered a sign of mTOR activation. But in this study, p70s6K was independently linked to hypertrophy.

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[themify_icon icon=”fa-quote-left”] The differential signalling pattern between mTOR and p70S6k suggests that p70S6kis activated via a pathway other than the one involving mTOR (Terzis et al., 2010)

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I’m not quite sure whether to put this study in the case against or case for hypertrophy. On one hand it shows us that mTOR downstream signals are linked to gains, but on the other hand it says these signals function independently of mTOR. It raises the possibility that we can get gains without mTOR activation.

In addition to the studies mentioned, several other researcher teams find correlations between p70s6K and gains 8. Others find a weak correlation between p70s6K and MyoMPS 9. It’s possible p70S6k is independent of mTOR, meaning mTOR might not be directly involved in some of the hypertrophic processes.

The case against mTOR

We will start the counterargument with Philp et al. challenging the assumption that molecular mechanisms like mTOR can predict gains by themselves:

It is likely that more than one factor is responsible for growth signaling in response to resistance exercise. It is possible that one sensor starts the cycle and the others function to maintain mTORC1 activity at various times after resistance exercise (…) in humans it is likely that many molecular signals are required to maintain or increase muscle mass (Philp et al., 2011).

The results of the present study suggest that p70S6K phosphorylation can regulate only a small rate of muscular growth [in humans], and that [other mechanisms are] required to gain a larger magnitude of hypertrophy (Nakada et al., 2016)

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Beyond this, some authors critique the idea that mTOR causes gains because endurance exercise can activate mTOR in humans (Murach and Bagley, 2016). If mTOR is an anabolic pathway and endurance exercise activates mTOR, does that mean endurance exercise is anabolic? Probably not. Perhaps mTOR can also initiate mitochondrial protein synthesis which is usually elevated after cardio (Mascher et al., 2011). But MitoMPS isn’t related to hypertrophic gains. We have a similar problem with older individuals. In a recent 2016 review, Timmons and Gallagher discuss that mTOR activation is elevated in fasted elderly people. This sounds very strange, since we would expect mTOR to be deactivated because (1) fasting = anti-mTOR and (2) aging = anabolic blunting. However, T & G explain that the mTOR activation is probably a “compensatory response reflecting increased relative muscle loading in daily life (due to reduced muscle strength or conditioning)”. This is one example where the body has to upregulate an anabolic mechanism because it’s, paradoxically, having problems maintaining muscle mass and/or function.

Three years ago, Philips et al. published a study where they looked molecular networks and genes in 45 untrained participants. They analyzed anabolic signalling mechanisms to predict gains to a 20 week, monitored resistance training protocol. The cool thing was that they analyzed every individual in isolation, because humans have very different responses to exercise 11. This is a different approach to most studies who lump all subjects together into one analysis and ignore individual differences in signalling mechanism activation and gains. Surprisingly, the research team found that those with the greatest hypertrophy did not “require” mTOR activation 12.

[expand title=”11“][themify_icon icon=”fa-quote-left”]The justification for this approach was based on the marked heterogeneity in capacity for muscle growth in humans, with gains ranging from 0% to 22% (Philips et al., 2013)

Conclusion

Several researchers now question whether anabolic signalling mechanisms can predict hypertrophy at all, because the body is so complicated and so many of its anabolic signals are interconnected 13. The signals might function non-linearly; activation of p70s6K/mTOR might predict gains when measured 1 hour after exercise, but perhaps not 2 hours after exercise. Perhaps another signalling pathway takes over and continues the work towards hypertrophy (Schoenfeld, 2013; Camera et al., 2016). But then again, the body can send as many anabolic signals as it wants to; without proper recovery and nutrition it won’t be able to grow. This shows us how futile it is to tunnel-vision on singular anabolic mechanisms without analysing your lifestyle, diet, sleep, diseases, etc.

[expand title=”13“][themify_icon icon=”fa-quote-left”] we may have to face the prospect that seeking ‘master regulators’ such as AMPK, AKT and mTOR in humans is naive and that spreading our nets wider, i.e. to encompass genomic mRNA/miRNA measures, is necessary to truly understand the role of protein turnover in determining heterogeneity in adaptive specificity and capacity (Atherton & Smith 2012).